1. Field of Invention
The size-selective porous polymeric adsorbents of this invention are biocompatible and hemocompatible and are designed to function in direct contact with body fluids. These adsorbents are useful in conjunction with hemodialysis for extracting and controlling the blood level of β2-microglobulin without significantly perturbing the levels of albumin, immunoglobulins, leukocytes, erythrocytes, and platelets. These polymeric adsorbents are also very effective in extracting cytokines from the blood of patients with sepsis while keeping the physiologically required components of blood at clinically acceptable levels. These adsorbents are also useful for purification of blood plasma by their ability to remove selectively small to midsize protein toxins without disturbing the level of the other plasma components.
2. Description of Related Art
Techniques of extracorporeal blood purification are important in many medical treatments including hemodialysis, hemofiltration, hemoperfusion, plasma perfusion and combinations of these methods. Hemodialysis and hemofiltration involve passing whole blood through hollow fibers to remove excess water and compounds of small molecular size but are unable to remove protein toxins such as beta-2-microglobulin (B2M) and the cytokines. Hemoperfusion is passing whole blood over an adsorbent to remove contaminants from the blood. Plasma perfusion is passing blood plasma through an adsorbent. In hemoperfusion, the treated whole blood returns to the patient's blood circulation system.
In addition to the common requirements such as hemocompatibility and sterility for medical devices, an ideal adsorbent for hemoperfusion and plasma perfusion should have an adsorption capacity and selectivity adequate for adsorbing toxins to the exclusion of useful components in order to be beneficial to the patient.
Conventional adsorbing materials include activated carbon, silicates, diatomite and synthetic porous resins. Activated carbon has been reported in extracorporeal adsorption for treating schizophrenia (Kinney, U.S. Pat. No. 4,300,551; 1981). Various synthetic polymeric adsorbents have been disclosed for removing toxic shock syndrome toxin-1, bradykinin and endotoxin from blood (Hirai, et al. U.S. Pat. No. 6,315,907; 2001; U.S. Pat. No. 6,387,362; 2002, and U.S. Pat. No. 6,132,610; 2000), and for removing poisons and/or drugs from the blood of animals (Kunin, et al., U.S. Pat. No. 3,794,584; 1974). Adsorption by the above adsorbents is generally rather nonselective and, therefore, is limited to short term treatments.
Most commercial porous resins are synthesized either by macroreticular synthesis (Meitzner, et al., U.S. Pat. No. 4,224,415; 1980), such as Amberlite XAD-4® and Amberlite XAD-16® by Rohm and Haas Company or by hypercrosslinking synthesis [Davankov, et al. J. Polymer Science, Symposium No. 47, 95-101 (1974)], used to make the Hpersol-Macronet® resins by Purolite Corp. Many conventional polymeric adsorbents have a large pore surface and adsorption capacity but a lack of selectivity due to the broad distribution of pore sizes. Others are produced to adsorb small organic molecules or are not hemocompatible and therefore are not suitable for selective adsorption of midsize proteins directly from body fluids.
In order to enhance the hemocompatibility, many techniques involve coating the hydrophobic adsorbent with hydrophilic materials such as polyacrylamide and poly(hydroxyethylmethacrylate) (Clark, U.S. Pat. No. 4,048,064; 1977; Nakashima, et al., U.S. Pat. No. 4,171,283; 1979). A copolymer coating of 2-hydroxyethyl methacrylate with diethylaminoethyl methacrylate is reported by Watanabe, et al. (U.S. Pat. No. 5,051,185; 1991). Davankov, et al. (U.S. Pat. No. 6,114,466; 2000) disclosed a method of grafting to the external surface of porous polymeric beads hydrophilic monomers including 2-hydroxyethyl methacrylate, N-vinylpyrrolidinone, N-vinylcaprolactam and acrylamide. Recently, Albright (U.S. Pat. No. 6,884,829 B2; 2005) disclosed the use of surface active dispersants [including polyvinyl alcohol, poly(dimethylaminoethyl methacrylate), poly(vinylpyrrolidinone), and hydroxethylcellulose] during macroreticular synthesis to yield a hemocompatible surface on porous beads in a one step synthesis.
The internal pore structure (distribution of pore diameters, pore volume, and pore surface) of the adsorbent is very important to adsorption selectivity. A cartridge containing a packed bed of adsorbent with effective pore diameters ranging from 2 Å to 60 Å (Angstrom) was disclosed for hemoperfusion by Clark (U.S. Pat. No. 4,048,064; 1977). This pore size range was primarily specified for detoxification and preventing adsorption of anticoagulants, platelets and leukocytes from the blood but is inadequate for adsorbing midsize proteins such as cytochrome-c and beta-2-microglobulin. Similarly, coating inorganic adsorbents, such as silicate and diatomite, with a membrane film having pore sizes greater than 20 Å was disclosed by Mazid (U.S. Pat. No. 5,149,425; 1992) for preparing hemoperfusion adsorbents. More recently, Giebelhausen (U.S. Pat. No. 551,700; 2003) disclosed a spherical adsorbent with pronounced microstructure with 0-40 Å pore diameters and an overall micropore volume of at least 0.6 cm3/g for adsorption of chemical warfare agents, toxic gases and vapors, and refrigerating agents. The above pore structures are too small for adsorption of midsize proteins from physiologic fluids.
An adsorbent with a broad distribution of pore sizes (40˜9,000 Å diameter) was disclosed for adsorbing proteins, enzymes, antigens, and antibodies by Miyake et al. (U.S. Pat. No. 4,246,351; 1981). The adsorbent sorbs both the toxins as well as the beneficial proteins such as albumin from the blood due to its broad pore size distribution. Immobilizing antibodies and IgG-binding proteins onto porous polymeric adsorbents were described to enhance selectivity of adsorbents having broad pore size distributions for lowering low density lipoproteins, for treating atherosclerosis, for adsorbing rheumatoid arthritis factor (Strahilevitz, U.S. Pat. No. 6,676,622; 2004), and for removing hepatitis C virus from blood (Ogino et al. U.S. Pat. No. 6,600,014; 2003). The antibodies or proteins bound to adsorbents, however, could greatly increase the side effects for a hemoperfusion or a plasma perfusion device and could greatly increase the difficulty for maintaining sterility of the devices.
Removal of beta-2-microglobulin by direct hemoperfusion was beneficial to renal patients (Kazama, “Nephrol. Dial. Transplant”, 2001, 16:31-35). An adsorbent with an enhanced portion of pores in a diameter range between 10 and 100 Å was described by Braverman et al. (U.S. Pat. No. 5,904,663; 1999) for removing beta-2-microglobulin from blood and by Davankov et al (U.S. Pat. No. 6,527,735; 2003) for removing toxins in the molecular weight range of 300-30,000 daltons from a physiologic fluid. Strom, et al. (U.S. Pat. No. 6,338,801; 2002) described a synthesis method for polymer resins with pore sizes in the range from 20 Å to 500 Å intended for adsorbing beta-2-microglobulin. The in-vitro study by the present inventors shows that the pore structures proposed by Davankov and Strom, however, are inadequate for a selective adsorption of midsize proteins such as beta-2-microglobulin and cytochrome-c in the presence of serum albumin.
In contrast to prior disclosures, the porous polymeric adsorbents specified in the present invention demonstrate a high selectivity for adsorbing small and midsize proteins to the exclusion of the large proteins with molecular weights greater than 50,000 daltons. More significantly, the present invention discloses adsorbents for hemoperfusion suitable for long term clinical treatment, since the healthy components such as albumin, red blood cells, platelets and white blood cells are maintained at clinically acceptable levels.